1.8. ALKYLATION OF ALDEHYDES, ESTERS, AMIDES, AND NITRILES

1. 1.8. ALKYLATION OF ALDEHYDES, ESTERS, AMIDES, AND NITRILES Methods for the alkylation of enolates of esters, amides, and nitriles have also been developed. • Alkylation of aldehyde enolates is not very common, also because aldehydes are rapidly converted to aldol condensation products by base. • Only when the enolate can be rapidly and quantitatively formed, aldol condensation is avoided (for example KNH2/NH3and KH/THF). • Alkylation via enamines or enamine anions provides a more general method for alkylation of aldehydes.

2. Alkylations of simple esters require a strong base because relatively weak bases such as alkoxides promote condensation reactions. • The successful formation of ester enolates typically involves an amide base, usually LDA or potassium hexamethyldisilylamide (KHMDS) at low temperature. The resulting enolates can be successfully alkylated with alkyl bromides or iodides. HMPA is sometimes added to accelerate the reaction.

3. Carboxylic acids can be directly alkylated by conversion to dianions by two equivalents of LDA. The dianions are alkylated at the a carbon as would be expected. A method for enantioselective synthesis of carboxylic acid derivatives is based on alkylation of the enolates of N-acyl oxazolidinones. The lithium enolates have the structures shown because of the tendency for the metal cation to form a chelate.

4. In first molecule the upper face is shielded by the isopropyl group whereas in the second the lower face is shielded by the methyl and phenyl groups. • As a result, alkylation of the two derivatives gives products of the opposite configuration. • Subsequent hydrolysis or alcoholysis provides acids or esters in enantiomerically enriched form. The initial alkylation product ratios are typically 95 : 5 in favor of the major isomer. • Because the intermediates are 3:1 diastereomeric mixtures, they can be separated. The final products can then be obtained in >99% enantiomeric purity.

5. Acetonitrile (pKDMSO = 31.3) can be deprotonated, provided a strong nonnucleophilic base such as LDA is used. Phenylacetonitrile (pKDMSO = 21.9) is considerably more acidic than acetonitrile. Deprotonation can be done with sodium amide. Dialkylation has been used in the synthesis of meperidine, an analgesic substance.

6. IMINES AZOMETHINES SCHIFF BASES VINYLAMINES ENAMINES 1.9. The Nitrogen Analogs of Enols and Enolates-Enamines and Imine Anions The nitrogen analogs of ketones and aldehydes are called imines, azomethines, or Schiff bases. These compounds can be prepared by condensation of primary amines with ketones and aldehydes. When secondary amines are heated with ketones or aldehydes in the presence of an acidic catalyst, a related condensation reaction occurs and can be driven to completion by removal of water by azetropic distillation or use of molecular sieves. The condensation product is a substituted vinylamine or enamine.

7. There are other methods for preparing enamines from ketones that utilize strong dehydrating reagents to drive the reaction to completion. • For example, mixing carbonyl compounds and secondary amines followed by addition of titanium tetrachloride rapidly gives enamines. This method is especially applicable to hindered amines. • Triethoxysilane can also be used. Another procedure involves converting the secondary amine to its N-trimethylsilyl derivative. Because of the higher affinity of silicon for oxygen than nitrogen, enamine formation is favored and takes place under mild conditions.

8. The b-carbon atom of an enamine is a nucleophilic site because of conjugation with the nitrogen atom. Protonation of enamines takes place at the b-carbon, giving an iminium ion. The nucleophilicity of the b-carbon atoms permits enamines to be used in synthetically useful alkylation reactions:

9. The enamines derived from cyclohexanones have been of particular interest. The pyrrolidine enamine is most frequently used for synthetic applications. In the enamine mixture formed from pyrrolidine and 2-methylcyclohexanone, the structure on the left is predominant. • The tendency for the less substituted enamine to predominate is quite general. A steric effect is responsible for this preference. Conjugation between the nitrogen atom and the p orbitals of the double bond favors coplanarity of C=C-N system. A serious nonbonded repulsion (A1,3 strain) destabilizes the other isomer. • Furthermore, in the first isomer the methyl group adopts a quasi-axial conformation to avoid steric interaction with the amine substituents.

10. ALKYLATION TO THE LESS SUBSTITUTED a CARBON ENAMINE Because of the predominance of the less substituted enamine, alkylations occur primarily at the less substituted a carbon. Synthetic advantage can be taken of this selectivity to prepare 2,6-disubstituted cyclohexanones. The iminium ions resulting from C-alkylation are hydrolyzed in the workup procedure. KETONE

11. Alkylation of enamines requires relatively reactive alkylating agents for good results. • Methyl iodide, allylic and benzylic halides, a-haloesters, a-haloethers, and a-haloketones are the most successful alkylating agents. • Enamines also react with electrophilic alkenes.

12. Imines can be deprotonated at the a carbon by strong bases to give the nitrogen analogs of enolates. Originally, Grignard reagents were used for deprotonation, but LDA is now commonly used. These anions are usually referred to as imine anions or metalloenamines. Imine anions are isoelectronic and structurally analogous to both enolates and allylanions and can also be called azaallyl anions. • Spectroscopic investigations of the lithium derivatives of cyclohexanone N-phenylimine indicate that it exists as a dimer in toluene. • If a better donor solvent as THF, is added, equilibrium with a monomeric structure is established. • The monomer is favored at high THF concentrations.

13. more nucleophilic than more nucleophilic than imine anions enamines enols enolates Just as enamines are more nucleophilic than enols, imine anions are more nucleophilic than enolates and react efficiently with alkyl halides. Two applications of imine anions in the alkylation of aldehydes.

14. Ketone imine anions can also be alkylated. The prediction of the regioselectivity of lithioenamine formation is somewhat more complex than for the case of kinetic ketone enolate formation. One of the complicating factors is that there are two imine stereoisomers, each of which can give rise to two regioisomeric imine anions. The isomers in which the nitrogen substituent R' is syn to the double bond are the more stable.

15. For methyl ketimines, good regiochemical control in favor of methyl deprotonation, regardless of imine stereochemistry, is observed using LDA at -78°C. With larger substituents, deprotonation at 25°C occurs anti to the nitrogen substituent.

16. However, the syn and anti isomers of imines are easily thermally equilibrated. They cannot be prepared as single stereoisomers directly from ketones and amines, so this method cannot be used to control regiochemistry of deprotonation. • By allowing lithiated ketimines to come to room temperature, the thermodynamic composition is established. The most stable structures are those shown below, which in each case represent the less substituted isomer. The complete interpretation of regiochemistry and stereochemistry of imine deprotonation also requires consideration of the state of aggregation and solvation of the base.

17. One of the most useful aspects of the imine anions is that they can be readily prepared from enantiomerically pure amines. • When imines derived from these amines are alkylated, the new carbon-carbon bond is formed with a bias for one of the two possible stereochemical configurations. • Hydrolysis of the imine then leads to enantiomerically enriched ketone. The interpretation and prediction of the relationship between the configuration of the newly formed chiral center and the configuration of the amine are usually based on steric differentiation of the two faces of the imine anion. Most imine anions that show high stereoselectivity incorporate a substituent which can hold the metal cation in a compact transition state by chelation.

18. In this example enantioselectivity is rationalized on the basis of the structure of the transition state. The fundamental features of this transition state are • the chelation of the methoxy group with the lithium ion, which establishes a rigid transition state; • the interaction of the lithium ion with the bromide leaving group; • the steric effect of the benzyl group, which makes the underside the preferred direction of approach for the alkylating agent.

19. Hydrazones can also be deprotonated to give lithium salts which are reactive toward alkylation at the b carbon. • Hydrazones are more stable than alkylimines and therefore have some advantages in synthesis. • The N,N-dimethylhydrazones of methyl ketones are kinetically deprotonated at the methyl group. • This regioselectivity is independent of the stereochemistry of the hydrazone. • Two successive alkylations of the N,N-dimethylhydrazone of acetone can provide unsymmetrical ketones.

20. The anion of cyclohexanone N,N-dimethylhydrazones shows a strong preference for axial alkylation. • 2-Methylcyclohexanone N,N-dimethylhydrazone is alkylated by methyl iodide to give cis-2,6-dimethylcyclohexanone. • The methyl group in the hydrazone occupies a pseudoaxial orientation. Alkylation apparently is preferred anti to the lithium cation, which is on the face opposite to the 2-methyl substituent. Chiral hydrazones have also been developed for enantioselective alkylation of ketones. The hydrazones can be converted to the lithium salt, alkylated, and then hydrolyzed to give alkylated ketone in good chemical yield and with high enantioselectivity.

21. A procedure for enantioselective synthesis of carboxylic acids is based on sequential alkylation of oxazolines via the lithium salt. Chelation by the methoxy group leads preferentially to the transition state in which the lithium is located as shown. The lithium acts as a Lewis acid in directing the approach of the alkyl halide. This is reinforced by a steric effect from the phenyl substituent. As a result, alkylation occurs predominantly from the lower face of the anion. The sequence in which the groups R and R' are introduced determines the chirality of the product. The enantiomeric purity of disubstituted acetic acids obtained after hydrolysis is in the range of 70-90%.

22. 1.10 Alkylation of Carbon Nucleophiles by Conjugate Addition Another important method for alkylation of carbon involves the addition of a nucleophilic carbon species to an electrophilic multiple bond. • The electrophilic reaction partner is typically an a,b-unsaturated ketone, aldehyde, or ester, but other electron-withdrawing substituents such as nitro, cyano, or sulfonyl also activate carbon-carbon double and triple bonds to nucleophilic attack. • The reaction is called conjugate addition or the Michael reaction. Other kinds of nucleophiles such as amines, alkoxides, and sulfide anions also react similarly, but we will focus on the carbon-carbon bond forming reactions.

23. In contrast to the reaction of an enolate anion with an alkyl halide, which requires one equivalent of base, conjugate addition of enolates can be carried out with a catalytic amount of base. All the steps are reversible.

24. When a catalytic amount of base is used, the reaction proceeds with thermodynamiccontrol of enolate formation. The most effective nucleophiles under these conditions are carbanions derived from relatively acidic compounds such as b-ketoesters or malonate esters. The adduct anions are more basic and are protonated under the reaction conditions. • Effective catalysts for particular cases are • fluoride ion for Michael additions involving relatively acidic carbon compounds; • aluminum tris(2,6-diphenylphenoxide) for additions of enolates to enones.

25. Conjugate addition can also be carried out by completely forming the nucleophilic enolate under kinetic conditions. Ketone enolates formed by reaction with LDA in THF react with enones to give 1,5-diketones. Esters of 1,5-dicarboxylic acids are obtained by addition of ester enolates to a,b-unsaturated esters

26. Z-Enolates anti adducts E-enolates syn adducts. There have been several studies of the stereochemistry of conjugate addition reactions. If there are substituents on both the nucleophilic enolate and the acceptor, either syn or anti adducts can be formed. The reaction shows a dependence on the E- or Z-stereochemistry of the enolate. These tendencies can be understood in terms of a chelated transition state.

27. Z-enolates anti adducts E-enolates syn adducts

28. When the conjugate addition is carried out under kinetic conditions with stoichiometric formation of the enolate, the adduct is also an enolate until the reaction mixture is quenched with a proton source. • It should therefore be possible to effect a second reaction of the enolate if an electrophile is added prior to protonation of the enolate. • This can be done by adding an alkyl halide to the solution of the adduct enolate, which results in an alkylation. Two or more successive reactions conducted in this way are referred to as tandem reactions. Tandem conjugate addition-alkylation has proven to be an efficient means of introducing both a and b substituents at enones.

29. Conditions for effecting conjugate addition in the presence of Lewis acids have also been developed. Trimethylsilyl enol ethers can be caused to react with electrophilic alkenes by use of TiCl4. These reactions proceed rapidly even at – 78°. Similarly, TiCl4 or SnCl4 induces addition of silyl enol ethers to nitroalkenes. The initial adduct is trapped in cyclic form by trimethylsilylation. Hydrolysis of this intermediate regenerates the carbonyl group.

30. Other Lewis acids can also effect conjugate addition of silyl enol ethers to electrophilic alkenes. For example, Mg(ClO4)2 catalyzes addition of ketene silyl acetals: Lanthanide salts have been found to catalyze addition of a-nitroesters, even in aqueous solution.

31. Cyanide ion acts as a carbon nucleophile in the conjugate addition reaction. An alcoholic solution of potassium or sodium cyanide is suitable for simple enones. Triethylaluminum-hydrogen cyanide and diethylaluminum cyanide are also useful reagents for conjugate addition of cyanide. The latter is the more reactive of the two reagents. These reactions presumably involve the coordination of the aluminum reagent as a Lewis acid at the carbonyl oxygen.

32. Enamines also react with electrophilic alkenes to give conjugate addition products. • The addition reactions of enamines of cyclohexanones show a strong preference for attack from the axial direction. • This is anticipated on stereoelectronic grounds because the p orbital of the enamine is the site of nucleophilicity.